CD8+ CTL priming by exact peptide epitopes in incomplete Freund's adjuvant induces a vanishing CTL response, whereas long peptides induce sustained CTL reactivity
CD8+ CTL priming by exact peptide epitopes in incomplete Freund's adjuvant induces a vanishing CTL response, whereas long peptides induce sustained CTL reactivity
复制标题
DOI：
10.4049/jimmunol.179.8.5033
复制
发表时间：
2007-10-15
影响因子：
4.4
通讯作者：
van der Burg, Sjoerd H.
中科院分区：
文献类型：
--
作者：
Bijker, Martijn S.;van den Eeden, Susan J. F.;van der Burg, Sjoerd H.
治疗性疫苗接种试验，其中癌症患者接种了水包油制剂中的最小CTL肽，取得了有限的成功。这些研究中有许多是基于小鼠研究的有希望的数据，表明用IFA中的短合成肽接种疫苗可产生保护性CD 8（+）T细胞免疫。通过在IFA中使用高免疫原性的OVA CTL肽作为基于肽的疫苗的模型，我们研究了为什么IFA中的最小CTL肽疫苗表现得如此不充分以允许肽疫苗接种的完全优化。在IFA中注射最小量的MHC I类结合OVA（257-264）肽瞬时激活了CD 8（+）效应T细胞，其最终未能经历二次扩增或杀死靶细胞，这是由于CTL肽的持续和全身呈递逐渐从IFA库中泄漏而没有全身危险信号。用MHC II类结合Th肽（OVA（323-339）.）恢复了CD 8（+）T细胞的二次扩增和体内效应子功能。简单地将CTL肽延长至30个氨基酸的长度也保留了这些CD 8（+）T细胞的功能，不依赖于T细胞的帮助，因为较长的CTL肽主要存在于局部发炎的引流淋巴结中。重要的是，这些功能差异在另外两个模型Ag系统中再现。我们的数据清楚地显示了为什么在IFA中用最小肽表位引发CTL是次优的，并证明了使用这些CTL肽表位的较长版本确保了体内持续效应CD 8（+）T细胞反应性的诱导。
Therapeutic vaccination trials, in which patients with cancer were vaccinated with minimal CTL peptide in oil-in-water formulations, have met with limited success. Many of these studies were based on the promising data of mice studies, showing that vaccination with a short synthetic peptide in IFA results in protective CD8(+) T cell immunity. By use of the highly immunogenic OVA CTL peptide in IFA as a model peptide-based vaccine, we investigated why minimal CTL peptide vaccines in IFA performed so inadequately to allow full optimization of peptide vaccination. Injection of the minimal MHC class I-binding OVA(257-264) peptide in IFA transiently activated CD8(+) effector T cells, which eventually failed to undergo secondary expansion or to kill target cells, as a result of a sustained and systemic presentation of the CTL peptides gradually leaking out of the IFA depot without systemic danger signals. Complementation of this vaccine with the MHC class II-binding Th peptide (OVA(323-339).) restored both secondary expansion and in vivo effector functions of CD8(+) T cells. Simply extending the CTL peptide to a length of 30 aa also preserved these CD8(+) T cell functions, independent of T cell help, because the longer CTL peptide was predominantly presented in the locally inflamed draining lymph node. Importantly, these functional differences were reproduced in two additional model Ag systems. Our data clearly show why priming of CTL with minimal peptide epitopes in IFA is suboptimal, and demonstrate that the use of longer versions of these CTL peptide epitopes ensures the induction of sustained effector CD8(+) T cell reactivity in vivo.